Distribution of cellular HSV-1 receptor expression in human brain

Abstract

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, including TNFRSF14/HVEM and PVRL1/nectin 1 as gD receptors and PILRA, MAG, and MYH9 as gB receptors. We investigated the expression of these receptor molecules in different areas of the adult and developing human brain using online transcriptome databases. Whereas all HSV-1 receptors showed distinct expression patterns in different brain areas, the Allan Brain Atlas (ABA) reported increased expression of both gD and gB receptors in the hippocampus. Specifically, for PVRL1, TNFRFS14, and MYH9, the differential z scores for hippocampal expression, a measure of relative levels of increased expression, rose to 2.9, 2.9, and 2.5, respectively, comparable to the z score for the archetypical hippocampus-enriched mineralocorticoid receptor (NR3C2, z = 3.1). These data were confirmed at the Human Brain Transcriptome (HBT) database, but HBT data indicate that MAG expression is also enriched in hippocampus. The HBT database allowed the developmental pattern of expression to be investigated; we report that all HSV1 receptors markedly increase in expression levels between gestation and the postnatal/adult periods. These results suggest that differential receptor expression levels of several HSV-1 gD and gB receptors in the adult hippocampus are likely to underlie the susceptibility of this brain region to HSV-1 infection.

Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections—a Nationwide, Population-Based Cohort Study in Taiwan

“…In 1982, Ball first suggested that HSV-1 might be involved in the pathogenesis of AD by finding that the brain regions damaged in HSV encephalitis, the limbic system, are the same as those affected the earliest in AD [35]. This is reinforced by the finding that receptors for HSV-1 are selectively expressed in the limbic system [36]. Several other studies have shown that HSV-1 and being a carrier of the apolipoprotein E allele 4 (ApoE e4) together confer risk for AD [9,11,27,[37][38][39].…”

Paired Immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease

“…HSV-1 has been implicated in AD pathogenesis by several lines of evidence, including the presence of HSV-1 viral DNA in human brain tissue [51,52], increased HSV-1 seropositivity in AD cases [53][54][55][56], the correlation of high avidity HSV-1 antibodies with protection from cognitive decline [56], the binding of HSV-1 gB to APOE-containing lipoproteins [57], HSV-1-induced amyloidogenic processing of amyloid precursor protein (APP) [58][59][60], and preferential targeting of ADaffected regions in HSV-1 acute encephalitis [61]. In addition, HSV-1 gD receptors and gB receptor PILRA increase with age in multiple brain regions, including the hippocampus [62]. Additional AD risk loci have been proposed to play a role in the life cycle of HSV-1 [63], including CR1, which is capable of binding HSV-1 [64].…”

Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer’s Disease

“…Lathe and Haas ( 2017 ) found increased expression of host cell viral entry receptors for HSV-1 glycoproteins gD and gB within the hippocampus using gene expression profiling from the microarray based Allen Human Brain Atlas and Human Brain Transcriptome database. The hippocampus demonstrated significantly increased gene expression of host cell viral entry receptor proteins PVRL1, TNFRFS14 and MYH9 when tested across the whole human brain.…”